The understanding of human health has advanced tremendously in the past decades. However, detailed quantitative understanding is still in a crucial need. For example, understanding is needed of the control and mediation of life processes by G-Proteins, where the complexes of these proteins with their cofactors regulate signal transduction and transport processes. Similarly, important is the understanding of the use of ATP in specialized proteins to fuel biological machines and to control key processes. A related issue that requires detailed understanding is the problem of directional motions of biological motors that generate directional force in muscular, cardiac and neural cells that are often involved in diseases due to faulty functions. This project is aimed at a concerted attempt to use multiscale modeling in order to quantify the understanding of the structure/function correlation of systems that use G-proteins and ATPase. Such an understanding should have significant help in fighting diseases.
Our previous studies developed methods for studying the GTPase reaction in solution, in RasGAP and in EF-Tu. The simulations explored the key role of mutations lead to cancer and identified the underlined allosteric mechanism. In order to confirm our finding we performed major ab initio QM/MM studies of the reference solution reaction and evaluated the surface in RasGAP and EF-Tu, confirming our conclusions about the electrostatic catalytic effect. We also made major progress in studying the biological motors, FOF1-ATP synthase and myosin V.
In considering the scientific impact of our project we note that understanding the detailed action of G-proteins can have far reaching impact on understanding cellular processes. For example, finding a way to accelerate the GTPase reaction and to turn on cancer causing RasGAP mutants can provide key clues for the design of anticancer drugs. Furthermore, understanding the action of GPCRs or the elongation cycle of EF-Tu and EF-G is of major importance. The simulations have provided insights into the action of G-proteins and thus yielded an important element in the study of biological signal transduction. The focus on the systematic modeling of phosphoryl transfer in solution by ab initio approaches has drawn the attention of the theoretical community to the key problems in the field. Finally, the studies of allosteric effects in G-Proteins should eventually provide a better understanding of the control of signal transduction, and help in the design of effective drugs against devastating diseases.

  • Studies of the Molecular Origin of Cancers and Signal Transduction Processes:
    • ras-p21 and other GTP and ATP hydrolyzing enzymes
    • EF_Tu_active.pdb
    • protein-protein interaction: Affinity and Specificity

    • References:
    • - R.B. Prasad, N.V. Plotnikov, J. Lameira & A. Warshel (2013) Quantitative exploration of the molecular origin of the activation of GTPase. Proceedings of the National Academy of Sciences of the United States of America 110(51):20509, DOI:10.1037/pnas.1319854110.

      - A. J. Adamczyk & A. Warshel (2011) Converting Structural Information into an Allosteric-Energy-Based Picture for Elongation Factor Tu Activation by the Ribosome. Proceedings of the National Academy of Sciences of the United States of America 108(24):9827, DOI:10.1073/pnas.1105714108.

      - A. Shurki & A. Warshel (2004) Why Does the Ras Switch "Break" by Oncogenic Mutations? Proteins-Structure Function and Bioinformatics 55(1):1, DOI:10.1002/prot.20004.

      - T. M. Glennon, J. Villa, & A. Warshel (2000) How Does Gap Catalyze the Gtpase Reaction of Ras?: A Computer Simulation Study. Biochemistry 39(32):9641, DOI:10.1021/bi000640e.

      - T. Schweins & A. Warshel (1996) Mechanistic Analysis of the Observed Linear Free Energy Relationships in P21(Ras) and Related Systems. Biochemistry 35(45):14232, DOI:10.1021/bi961119g.